A conventional process for synthesis of 1-alkylthio- or 1-arylthiomethanediphosphonic acid is described, for example, in Japanese Examined Patent Publication (Kokoku) No. 4-29676. In the process shown therein, tetraalkyl methanediphosphoniate is converted to a corresponding metal derivative by sodium hydride and the like, and then various disulfides are allowed to react with the derivative to synthesize the objective tetraalkyl 1-alkylthio- or 1-arylthiomethanediphosphonate. Since this synthetic process gives the product in a low yield, a large amount of the recovered disulfide and tetraalkyl methanediphosphonate as well as a byproduct of the reaction, thiol, exist with the objective compound in a crude product, and an industrially expensive purification process, such as silica gel column chromatography, is needed for removing these impurities. Considering the fact that the objective methanediphosphonic acid compounds are highly useful in pharmaceutical fields, the above-mentioned process is not satisfactory to provide a large amount of the compound, and therefore a simple, economical process is required.
The greatest problem in the synthetic process described in Japanese Examined Patent Publication (kokoku) No. 4-29676 is that a large amount of starting material, tetraalkyl methanediphosphonate, was recovered unchanged, resulting in significant labor-consumption for the separation and purification of the objective product from the starting material. If the remaining methanediphosphonate in the reaction mixture can be reduced, this process will be an excellent process for producing 1-alkylthio- or 1-arylthiomethanediphosphonic acid. As the result of detailed investigation of the condensation of tetraalkyl methanediphosphonate with disulfide, the present inventors found that the objective product, tetraalkyl 1-alkylthiomethanediphosphonate or tetraalkyl 1-arylthiomethanediphosphonate, can be obtained in an extremely high yield, by removing the byproduct, alkylthiolate or arylthiolate which is formed in amounts equimolar with the objective product. In addition, it is found that the addition of a metal oxide including magnesium oxide to the synthetic process also provides the objective tetraalkyl 1-alkylthiomethanediphosphonate or tetraalkyl 1-arylthiomethanediphosphonate in a high yield.
Accordingly, it is an object of the present invention to provide a novel process for production of a 1-alkylthiomehanediphosphonic acid compound or 1-arylthiomehanediphosphonic acid compound, which is extremely useful as pharmaceuticals.